This section provides background information which is not necessarily prior art and a general summary of the present disclosure which is not a comprehensive disclosure of its full scope or all of its features.
CD24 is known as the heat-stable antigen (1). It is expressed as a glycosyl-phosphatidyl-inositol (GPI)-anchored molecule (2) and has a wide distribution in different lineages (3). Because of the tendency of CD24 to be expressed on immature cells, it has also been used as part of stem cell markers and for lymphocyte differentiation. The first function associated with CD24 is a costimulatory activity for antigen-specific T cell response (4-6). In vivo studies indicated that, as a costimulator for T cell activation in the lymphoid organ, CD24 is redundant but becomes essential in the absence of CD28 (7, 8). This would not be the case for local target organs that are not as “costimulator rich”. Consistent with this notion, we demonstrated that mice with a targeted mutation of CD24 are completely resistant to induction of experimental autoimmune encephalomyelitis (EAE) (9) (10).
Polymorphisms of human CD24 are associated with risk and progression of several autoimmune diseases (11-15), including multiple sclerosis and rheumatoid arthritis (RA). In cases of multiple sclerosis, we have reported that soluble CD24, consisting of the extracellular portion of murine CD24 and human IgG1 Fc ameliorated the clinical symptom of experimental autoimmune diseases, the mouse model of multiple sclerosis (9). More recent studies by one of us demonstrated that CD24 interact with and represses host response to danger-associated molecular patterns (DAMPs) (16).
RA affects 0.5-1% of human populations. Although a number of disease-modifying antirheumatic drugs (DMARDs) are currently available, even the gold standard of biologic DMARDs, the therapeutics targeting the tumor-necrosis factor alpha, lead to 50% improvement according to American College of Rheumatology Improvement Criteria (ACR50) in less than 50% of the patients receiving the treatments (17). No cure for RA is available. It is therefore necessary to test additional therapeutics for RA. RA is presumed to be autoimmune diseases in the joint, although the cause of the diseases remains largely obscure. A number of studies have implicated T cells in the pathogenesis of rheumatoid arthritis (18). More recently, it has been demonstrated that transfer of antibodies can cause the development of inflammation of the joints of mice (19-21). The pathology of the lesions resembles human rheumatoid arthritis.
One of the most interesting concepts established from the study with passive transfer of RA by antibodies is that tissue-specific autoimmune diseases can be observed even if the antibodies are specific for proteins that are ubiquitously expressed (19-21). This notion is important as it suggest that despite shared pathogenesis, autoimmune diseases to different organs/tissues may require different treatment. In support of this notion, interferon β, which is widely used for treatment of multiple sclerosis, show little effect for treatment of RA (22).
Animal models relevant to human RA played an important role for the advancement of therapeutic development in DMARDs. For example, collagen-induced arthritis in the mouse and rat were critical for the development of therapeutics for RA (23). More recently, it has been demonstrated that adaptive transfer of anti-collagen antibodies cause robust RA-like lesion in the mice (19). Since auto-antibodies are elevated in RA patients prior to the onset of diseases (24, 25), passive transfer of collagen-specific antibody is a relevant model for human RA.
Since the pathogenesis of RA involves host response to DAMP (26, 27) and since the CD24 molecule negatively regulate host response to DAMPs (16), we investigated the potential of using soluble CD24 to treat RA. The passive transfer model of RA was chosen because of both relevance to human diseases and simplicity of experimental designs.